Synthesis of pyrrolidones and quinolines from the known biomass feedstock levulinic acid and amines

Article abstract of DOI:10.1016/j.tetlet.2016.01.018

The catalytic conversion of biomass-derived compounds into value-added products such as food additives, agrochemical components, and pharmaceutical formulations, is a promising and cost effective synthetic strategy. Here, we describe the synthesis of a variety of N-(alkyl, aryl)-5-methyl-2-pyrrolidones through the reductive amination of levulinic acid using formic acid as the hydrogen source. This system is catalyzed by 3.8 nm ruthenium nanoparticles that were prepared by thermal decomposition of [Ru₃(CO)₁₂] in solvent-free conditions. When the reactions were carried out without the catalyst, the pyrrolidones were obtained with low yield and poor selectivity. In addition, the reaction between levulinic acid and 2-ethynylaniline produced 2-(2,4-dimethylquinolin-3-yl) acetic acid (8) in mild and metal-free conditions with good yield. Furthermore, the synthesis of substituted quinolines was achieved through a condensation reaction between levulinic acid and different 2-alkynylanilines promoted by p-toluenesulfonic acid, this method is highlighted as a novel procedure for the preparation of quinolines.

Full text of DOI:10.1016/j.tetlet.2016.01.018

Accepted Manuscript
Synthesis of Pyrrolidones and Quinolines from the Known Biomass Feedstock
Levulinic Acid and Amines
Carmen Ortiz-Cervantes, Marcos Flores-Alamo, Juventino J. García
PII:
S0040-4039(16)30019-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.018
TETL 47182
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 December 2015
28 December 2015
6 January 2016
Please cite this article as: Ortiz-Cervantes, C., Flores-Alamo, M., García, J.J., Synthesis of Pyrrolidones and
Quinolines from the Known Biomass Feedstock Levulinic Acid and Amines, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.01.018
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Synthesis of Pyrrolidones and Quinolines from the Known Biomass
Feedstock Levulinic Acid and Amines
Carmen Ortiz-Cervantes, Marcos Flores-Alamo and Juventino J. García*
Facultad de Química. Universidad Nacional Autónoma de México. México D. F. 04510
México
juvent@unam.mx
Abstract
The catalytic conversion of biomass-derived compounds into value-added products such as
food additives, agrochemical components and pharmaceutical formulations, is a promising
and cost effective synthetic strategy. Here, we describe the synthesis of a variety of N-
(alkyl, aryl)-5-methyl-2-pyrrolidones through the reductive amination of levulinic acid
using formic acid as the hydrogen source. This system is catalyzed by 3.8 nm ruthenium
nanoparticles that were prepared by thermal decomposition of [Ru3(CO)12] in solvent-free
conditions. When the reactions were carried out without the catalyst, the pyrrolidones were
obtained with low yield and poor selectivity. In addition, the reaction between levulinic
acid and 2-ethynylaniline produced 2-(2,4-dimethylquinolin-3-yl) acetic acid (8) in mild
and metal-free conditions with good yield. Furthermore, the synthesis of substituted
quinolines was achieved through a condensation reaction between levulinic acid and
different 2-alkynylanilines promoted by p-toluenesulfonic acid, this method is highlighted
as a novel procedure for preparation of quinolines.
Keywords: amines; cyclization, heterocycles, levulinic acid; quinolines; reductive
amination; ruthenium nanoparticles.
1

Introduction
Pyrrolidones such as 5-methyl-N-(methyl, aryl, or cyclohexyl)-2-pyrrolidones are value-
added products that have been widely used as solvents, surfactants, chelating agents,
agrochemical components, transdermal patches or pharmaceutical formulations.1
The transformation of oxo-carboxylic acid compounds to pyrrolidones by reductive
amination with ammonia was for the first time in the 1960s by Shilling.2 Then, in several
patents, Manzer described the reductive amination of levulinic acid (LA) under high
hydrogen pressure via heterogeneous catalysts.3 Very recently, Shimizu and co-workers
reported the reductive amination of LA with H2 catalysis supported by Pt catalysts under
solvent-free conditions.4
Of the variety of biomass-derived feedstocks, levulinic acid is potential chemical platform
with a broad range of applications.5 Formic acid (FA)6 and levulinic acid7 can be obtained
from biomass compounds such as cellulose, and FA is an efficient and reversible storage
material for hydrogen under very mild reaction conditions in the presence of the suitable
catalysts.8 Moreover, FA has been used for the reductive amination of LA as an alternative
to hydrogen pressure with Au heterogeneous catalysts;9 several ruthenium sources with
phosphine ligands as catalysts have been tested in the production of pyrrolidones from LA
with FA. Including the use of Ru(p-cymene)Cl22 with PtBuHBF4 offers a high yield but
limited scope.10
Recently, Wang and co-workers reported the use of iridium catalysts in transfer
hydrogenation to produce pyrrolidones by reductive amination of LA with an excess of
FA.11 The same group also reported metal-free synthesis of pyrrolidones in DMSO but with
a stoichiometric amount of NEt3.12 In addition, Andrioletti and co-workers reported another
2

example of metal-free reductive amination of LA; however, the reaction required more
forceful conditions including higher temperatures (160 – 200 °C).13
On the other hand, quinolines are an important heterocyclic compound due to their
antibacterial,14 anthelmintic15 and anti-inflammatory properties.16 There is a vast literature
on quinoline-derived compound syntheses. Several syntheses are based on the Friedländer
strategy with 2-aminobenzaldehyde and acetaldehyde17 as well as the reaction among
various anilines including those with -keto esters,18 alkynes,19 ethyl vinyl ether,20 ,-
unsaturated carbonyl compounds21 have been reported.22
In this work, we disclose the preparation of pyrrolidones by reductive amination using the
formic acid dehydrogenation catalyzed with Ru-NPs to obtain a variety of 5-methyl-N-
(aryl, alkyl)-2-pyrrolidones under solventless conditions in high yields. In addition, the first
metal-free synthesis of quinoline-derived compounds such as 2-(2,4-dimethylquinolin-3-yl)
acetic acid (8) from a reaction between biomass-derived levulinic acid and alkynylanilines
is described.
Results and discussion
Reductive amination of LA was performed with cyclohexylamine and FA. The latter was
the hydrogen source and key results are summarized in Table 1. In addition to the results
shown at Tables 1 and 3 a wide variety of reaction conditions can be found in SI. Then we
selected the milder reaction conditions, shorter reaction times and better yields. In the
absence of catalyst (Table 1, entry 1), product 1a was obtained as a mixture but in the
presence of nanoparticle precursor [Ru3(CO)12], there was an increase in pyrrolidone yield.
Other pre-catalysts or catalyst precursors such as [(dtbpe)PdCl2] (dtbpe = 1,2-(bis-di-tert-
3

butylphosphino)ethane) and [H4Ru4(CO)12] were used and showed lower activity. The main
role of the corresponding catalyst is believed to involve formic acid decomposition to
produce hydrogen.
Table 1. Reductive amination of levulinic acid with formic acid and cyclohexylamine.
1 (%)[a]
2 (%)[a]
3 (%)[a] 4 (%)[a]
Entry
[cat]
Conv. (%)
-----
100
100
100
100
93
67
94
97
81
72
18
2
2
11
8
10
1
1
3
6
5
3
-
5
7
1
2
[Ru3(CO)12]
[Ru3(CO)12]
[H4Ru4(CO)12]
[(dtbpe)PdCl2]
3 [b]
4
5
[a] All yields (mole%) were determined by GC-MS. [b] Hg drop test (0.07 mmol).
The formation of Ru-NPs from thermal decomposition of [Ru3(CO)12] in solvent-free
conditions was shown via TEM micrographs (Figure 1). The Ru-NPs with a mean diameter
of ca. 3.8 nm catalyzed the formic acid decomposition. Previously, we reported the formic
acid decomposition to levulinic acid hydrogenation catalyzed by Ru-NPs.23
4

Figure 1. TEM image (20 nm scale) of Ru-NPs from thermal decomposition of
[Ru3(CO)12] under solvent-free conditions.
In general, products from reductive amination of LA with alkyl amines were obtained by
FA decomposition catalyzed by Ru-NPs in high yields (Table 2). Of note, amines with
bulky substituents did not favor pyrrolidone formation due to steric hindrance. This does
not allow nucleophile attack of the amine over the LA (entries 4 and 6).
5

Table 2. Reductive amination of levulinic acid with aliphatic amines
Conv. (%)[a]
1 (%)[a]
2 (%)[a]
3 (%)[a]
4 (%)[a]
Entry
amine (a-f)
1
100
97
1
2
-
2
100
97
3
-
-
3
100
88
12
-
-
4
t-Bu-NH2
s-Bu-NH2
100
38
-
-
61
5
6
100
83
90
33
-
-
-
10
38
12
With 0.2 mol% of nanoparticles precursor ([Ru3(CO)12]) [a] All yields (mole%) were
determined by GC-MS.
In both Tables 1 and 3, entry 1, the control experiments indicates that low yields were
obtained without the use of Ru-NPs (67% vs 43% respectively), in both cases the yield was
increased with the use of Ru-Nps (Tables 1 and 3, entry 2). However, the production of
pyrrolidone from cyclohexylamine (Table 1, entry 3) did not decrease during mercury drop
test vs. a 20% decrease in the benzyl pyrrolidone synthesis (Table 3, entry 3). Therefore,
we conclude that the N-cyclohexyl-5-methyl-2-pyrrolidone production is faster and affected
by mercury drop. On the other hand, a yield decrease in the reaction with benzylamine
confirms the formation of Ru-NPs inactivated by mercury.24
6

Table 3. Reductive amination of levulinic acid with FA and benzylamine.
Conv. (%)[a]
5 (%)[a]
43
6 (%)[a] 7 (%)[a]
Entry
[cat]
-----
100
100
100
41
16
1
2
3
[Ru3(CO)12]
93
73
3
4
[Ru3(CO)12]b
5
22
[a] All yields (mole%) were determined by GC-MS. [b] Hg drop test (0.07 mmol).
The reductive amination of LA was carried out using a variety of aromatic amines (Table
4) to produce the respective pyrrolidones. Regarding the electronic and steric properties of
amines, higher conversions were obtained with electron-donor substituents (entry 2) as in
the case of methyl group. The electron withdrawing groups such as CF3 substituent (entry
7) did not favor the reaction. In the case of amines with pyridine groups, position 4 is more
electron deficient than that in position 3. Thus, the latter showed a higher selectivity to the
pyrrolidone product.
Surprisingly, when 2-ethynylaniline was used, the main product was 2-(2,4-dimethyl-
quinolin-3-yl) acetic acid (8). This is a condensation product of LA and 2-ethynylaniline. In
light of this result, the same reaction conditions were assessed for a variety of
alkynylanilines (entries 12 – 14, Table 4). However, these amines were not soluble in the
reaction mixture and have a melting point over 130 ºC—thus, their reactivity was low. Of
note, the use of solvents such as THF, mesitylene and xylene resulted in very low
conversions. When alkynylanilines were used there was a poor pyrrolidone formation as
well as a reduction in the alkyne to trans-alkene transformation.
7

Table 4. Reductive amination of levulinic acid with aromatic amines
Conv. (%)[a]
5 (%)[a]
93
6 (%)[a]
7 (%)[a]
Entry
amine (a-n)
1
2
3
4
100
100
100
100
3
5
4
-
95
76
18
31
6
4
65
5
100
91
8
1
6
7
100
100
100
88
77
48
89
50
21
44
1
2
8
10
-
8
9
40
10
11
89
66
22
-
-
100
53(8)
12b
13b
70
46
40
-
-
35
11
-
-
-
-
14b
30
Using 0.2 mol% of nanoparticles precursor ([Ru3(CO)12]) [a]All yields (mole%) were
determined by GC-MS. [b] trans-alkene pyrrolidone, R = H, Me, OMe.
8

A mechanistic proposal for the reductive amination of LA is depicted in Scheme 1. First,
imine A forms from LA and the amine, and then the imine-enamine reaches equilibrium
with the concomitant dehydration process that produces equilibrium species B1 and B2.
The formic acid decomposition via ruthenium nanoparticles then generates hydrogen and
carbon dioxide. Finally, the hydrogenation of compound B produces the corresponding
pyrrolidone.
Scheme 1. Mechanistic proposal for reductive amination of LA.
A series of reaction conditions were explored to improve the yield of compound 8.
Compound 8 was prepared under metal-free conditions as depicted in Scheme 2. Initially,
the formation of compound 8 begins with the hydration of alkyne to the corresponding
ketone that produces the respective imine through condensation with LA. This finally leads
to the formation of the quinoline 8 as shown in Scheme 3 vide infra. Suitable crystals for
9

X-ray determination of 8 were obtained by slow evaporation of THF. Figure 2 displays the
corresponding ORTEP drawing.
Scheme 2. Condensation reaction of levulinic acid and 2-ethynylaniline.
Figure 2. ORTEP diagram for compound 8. The thermal ellipsoids are drawn at 50%
probability. Selected distances (Å) and angles ( ): C(1) – N(1) = 1.361(4), C(7) – C(8) =
1.379(4), C(7) – C(10) = 1.512(4), C(8) – C(9) = 1.422(4), C(8) – C(12) = 1.513(4), C(9) –
N(1) = 1.324(4), C(9) – C(11) = 1.501(4), C(12) – C(13) = 1.502(4), C(13) – O(1) =
1.203(4), C(13) – O(2) = 1.267(4); C(8) – C(7) – C(10) = 122.6(3); C(13) – C(12) – C(8) =
112.8(3); O(1) – C(13) – O(2) = 122.8(3); and C(9) – N(1) – C(1) = 119.9(3).
On the other hand, quinoline-derived compounds were synthetized using LA and 2-
alkynylanilines with a modest conversion using a previously reported methodology for 4-
alkyl-2,3-disubstitued quinolines promoted by p-toluenesulfonic acid.18 As shown in Table
5, the main product from the condensation reaction between LA and alkynylanilines was
10

the quinoline-derived compound as well as the ketone compound derived from the alkyne
hydration.
Table 5. Synthesis of quinoline-derived compounds from levulinic acid and 2-
alkynylanilines
Conv. (%)[a]
Entry
R
Q1
(%)[a]
48
38
12
Q2
ketone
I1
I2
others
(%)[a]
(%)[a]
(%)[a] (%)[a] (%)[a]
H
Me
OMe
89
77
37
7
6
9
3
3
0
18
16
5
1
2
3
12
12
8
1
2
3
[a] All yields (mole %) were determined by GC-MS.
A possible route to quinoline formation is presented in Scheme 3. First, the ketone is
produced by a hydration reaction promoted by the Brønsted acid p-TsOH.25 The
condensation then leads to the enamine equilibrium to produce the imine. Finally, the
cyclization product forms and its dehydrative aromatization to results in a quinoline
derivative.
11

Scheme 3. A possible route to the synthesis of quinoline-derived compounds
Conclusions
The catalytic conversion of biomass-derived levulinic acid into valuable pyrrolidones was
achieved via reductive amination with formic acid-produced hydrogen and catalyzed via
ruthenium nanoparticles. In addition, quinoline-derived compounds were prepared by a
novel method under metal-free conditions promoted by p-toluenesulfonic acid from the
condensation reaction between levulinic acid and alkynylanilines in good yields. The
quinoline compound from 2-ethynylaniline and LA produced 2-(2,4-dimethylquinolin-3-yl)
acetic acid selectively under mild, metal-free and solventless conditions.
ASSOCIATED CONTENT
 Supporting Information available. Includes experiments and relevant NMR
spectra, GC-MS determinations and Crystal data for 8.
12

AUTHOR INFORMATION
Corresponding Author
E-mail: juvent@unam.mx
Acknowledgements
We thank CONACYT (178265) and DGAPA-UNAM (IN-202516) for their financial
support. C. O-C also thanks CONACYT for a graduate studies grant. We thank Iván
Puente-Lee (USAI-UNAM) for TEM studies and Dr. Alma Arévalo for technical support.
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15

Graphical Abstract
Synthesis of Pyrrolidones and Quinolines from the Known Biomass Feedstock
Levulinic Acid and Amines
Carmen Ortiz-Cervantes, Marcos Flores-Alamo, and Juventino J. García*
Facultad de Química. Universidad Nacional Autónoma de México. México D. F. 04510 México
juvent@unam.mx